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REVIEW
Genetics of congenital hypothyroidism
S M Park, V K K Chatterjee
...............................................................................................................................
J Med Genet 2005;42:379–389. doi: 10.1136/jmg.2004.024158
Congenital hypothyroidism is the most common neonatal
metabolic disorder and results in severe
neurodevelopmental impairment and infertility if untreated.
Congenital hypothyroidism is usually sporadic but up to 2%
of thyroid dysgenesis is familial, and congenital
hypothyroidism caused by organification defects is often
recessively inherited. The candidate genes associated with
this genetically heterogeneous disorder form two main
groups: those causing thyroid gland dysgenesis and those
causing dyshormonogenesis. Genes associated with
thyroid gland dysgenesis include the TSH receptor in non-
syndromic congenital hypothyroidism, and Gsa and the
thyroid transcription factors (TTF-1, TTF-2, and Pax-8),
associated with different complex syndromes that include
congenital hypothyroidism. Among those causing
dyshormonogenesis, the thyroid peroxidase and
thyroglobulin genes were initially described, and more
recently PDS (Pendred syndrome), NIS (sodium iodide
symporter), and THOX2 (thyroid oxidase 2) gene defects.
There is also early evidence for a third group of congenital
hypothyroid conditions associated with iodothyronine
transporter defects associated with severe neurological
sequelae. This review focuses on the genetic aspects of
primary congenital hypothyroidism.
...........................................................................
C
ongenital hypothyroidism is detected at a
rate of 1 in 3000 to 4000 live births, making
it the most common congenital endocrine
disorder.1 On a worldwide basis, hypothyroidism,
including congenital forms, results most com-
monly from iodine deficiency. Otherwise con-
genital thyroid gland insufficiency results from
developmental abnormalities at any level of the
See end of article for
hypothalamic-pituitary-thyroid axis. Congenital
authors’ affiliations hypothyroidism is most commonly caused by
.......................
defects in thyroid development leading to thyroid
Correspondence to:
dysgenesis (85%), which in turn consists of
Dr S M Park, Department either thyroid agenesis (40% of all cases) or
of Clinical Genetics, Box failure of the gland to descend normally during
134, Addenbrooke’s
embryological development with or without
Hospital, Hills Road,
Cambridge CB2 2QQ, UK;
ectopy (40%), or hypoplasia of a eutopic gland.2
soo-mi.park@ The remaining cases are associated with either a
addenbrookes.nhs.uk goitre or a normal thyroid gland.3 Rarely, central
(secondary) hypothyroidism may be caused by
Received in revised form
pituitary or hypothalamic disease leading to
18 October 2004
Accepted for publication deficiency of thyrotropin (TSH) or thyrotropin
3 November 2004 releasing hormone (TRH), respectively, which
....................... will not be covered by this review.
379
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via the JMG Unlocked open access trial,
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Committee. For further information, see
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full/42/2/97
In mammals the thyroid gland is the first
glandular tissue to appear in development,
arising from two regions of the endodermal
pharynx which migrate and associate to become
the characteristic bi-lobed structure.4 The median
anlage, which eventually forms the follicular
cells, arises from the midline of the anterior
pharyngeal floor between the first and second
branchial arches, being visible from days 16 to 17
of human gestation. At the same time two lateral
anlagen (ultimobranchial bodies), which mainly
become the parafollicular calcitonin secreting C
cells but also contribute to a significant number
of follicular cells,5 develop as caudal projections
from the fourth or fifth pharyngeal pouches. The
thyroid gland begins to trap iodide and therefore
to secrete thyroid hormones only at 10 to 12
weeks of human gestation,4 with the trans-
placental passage of maternal thyroid hor-
mones before this being important for fetal
development.
The essential role of thyroid hormones in
central nervous system (CNS) maturation has
been clearly demonstrated,6 and congenital
hypothyroidism is eminently treatable by thyr-
oxine replacement. Screening for neonatal
hypothyroidism has therefore been established
on a worldwide basis, beginning in Canada
in 1974 and in the United Kingdom in 1982.
The development of infants with congenital
hypothyroidism has been revolutionised with
the institution of early and adequate treatment
afforded by screening, thereby preventing intel-
lectual impairment and infertility. This is wit-
nessed by the normal growth and neurological
development in affected children, and by a
dramatic increase in IQ, from an average of less
than 80 to the mean of the general population.7
Most cases of congenital hypothyroidism occur
sporadically. However, dyshormonogenetic cases
are often recessively inherited, and recent cohort
analyses estimate that approximately 2% of cases
with thyroid dysgenesis are familial.8 It is also
noteworthy that congenital hypothyroidism is
associated with an increased incidence of birth
defects, with surveys in the United Kingdom
reporting a non-thyroidal congenital anomaly
rate of 7% and an increased prevalence of
chromosomal anomalies (1.5%).9 10
The candidate genes associated with primary
congenital hypothyroidism can be divided into
Abbreviations: ERSD, endoplasmic reticulum storage
disease; NIS, sodium iodide symporter; PHP,
pseudohypoparathyroidism; PPHP, pseudopseudo-
hypoparathyroidism; PTH, parathyroid hormone;
TPO, thyroid peroxidase; TRH, thyrotropin releasing
hormone; TSH, thyroid stimulating hormone (thyrotropin)
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380 Park, Chatterjee

two main groups: those causing thyroid gland dysgenesis and
those associated with defects in the organification of iodide,
leading to dyshormonogenesis. Genes associated with thyroid
gland dysgenesis include those causing non-syndromic
congenital hypothyroidism (TSH receptor) and those causing
syndromic congenital hypothyroidism (TITF-1, TITF-2, PAX-8,
and Gsa). Genes associated with dyshormonogenesis include
those for thyroid peroxidase (TPO), thyroglobulin (TG), the
sodium iodide symporter (NIS), pendrin (PDS), and most
recently, thyroid oxidase 2 (THOX2). Recent evidence
suggests a third group of congenital hypothyroid conditions
associated with defects in the iodothyronine transporter,
MCT8, where hypothyroidism is associated with severe
neurological deficits.
In this review we will focus on the genetics of the primary
congenital hypothyroidism. We will summarise the different
phenotypes associated with the currently known genetic
defects and outline informative investigative management.
THYROID DYSGENESIS AND NON-SYNDROMIC
CONGENITAL HYPOTHYROIDISM
The TSH receptor gene (TSHR) encodes a transmembrane
receptor present on the surface of follicular cells which
mediates the effects of TSH secreted by the anterior pituitary
and is critical for the development and function of the
thyroid gland. It belongs to a subfamily of heptahelical G
protein coupled receptors that have a common structure
consisting of seven transmembrane segments, three extra-
cellular and three intracellular loops, an extracellular amino
terminal domain, and an intracytoplasmic carboxyl terminal
tail (fig 1).11 The actions of TSH on the thyrocyte occur
principally by receptor mediated activation of Gsa and
alterations in TSH signalling pathways could result in
defective thyroid development. The hyt/hyt mouse is homo-
zygous for a loss of function mutation in the fourth
transmembrane domain of the TSHR, resulting in hypothyr-
oidism and thyroid hypoplasia postnatally.16
In contrast to mouse models, where an intact TSH-TSHR
signalling pathway does not appear to be a prerequisite for
the development of a normal sized thyroid gland in utero,17
this pathway is clearly important for the development of a
normally sized fully differentiated gland in utero in
humans.18 Homozygous or compound heterozygous muta-
tions in the human TSHR gene resulting in TSH resistance
were first described in 1995.19 Since then, additional loss of
function TSHR mutations have been identified in other
families showing variable TSH resistance because of reduced
thyroid sensitivity to TSH (fig 1).20–32 In some of these
families, compensated TSH resistance was associated with
euthyroid hyperthyrotropinaemia and either a normal or a
hypoplastic thyroid gland.19 20 27 29–31 Mild or borderline
hypothyroidism, with greatly raised serum TSH associated
with low normal or slightly low thyroid hormone levels and a
normal thyroid gland, was seen in two families.21 22 At the
other end of the spectrum, severe hypothyroidism associated
with a hypoplastic thyroid gland or even apparent athyreosis
has been reported.23–26 28 32
Inactivating mutations of the human TSHR are therefore
associated with three phenotypes:
N fully compensated TSH resistance to TSH;
N partially compensated TSH resistance to TSH;
N severe uncompensated resistance to TSH.

subsequent generation of intracellular cyclic adenosine
monophosphate (cAMP).12 The human TSHR gene is located
on chromosome 14q31 and the extracellular domain of the
receptor is encoded by nine exons, whereas the transmem-
brane and intracellular portions are encoded by a single large
exon.13 14
The initiation of expression of the TSHR on day 14 of
mouse embryogenesis, at the onset of thyroid differentia-
tion after completion of gland migration,15 suggests that
In common with other G protein coupled receptors,
activating mutations have also been described in the TSHR,
causing thyroid hyperfunctioning adenomas when somatic,33
or non-autoimmune congenital hyperthyroidism with germ-
line abnormalities.34 It is of note that heterozygosity for a
TSHR mutation (W546X) is increasingly being reported in
families from a white background,20 21 32 35 with a rate of
approximately 0.6% in a cohort of euthyroid Welsh subjects.35
These results have therefore raised the possibility that the

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Figure 1 Cartoon of the TSH receptor showing the positions of all the loss of function mutations reported to date. Missense mutations are shown in the
circles, frameshift and deletion mutations are indicated by arrows, and splice site mutations are marked.

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Genetics of congenital hypothyroidism
mutation may contribute to thyroid dysfunction in that
population, though this is very unlikely in the homozygous
state.
There have also been reports of mildly raised TSH levels in
individuals who are heterozygous for loss of function
germline mutations in the TSHR.19 27 30–32 All have been
reported to have normal sized eutopic thyroid glands on
ultrasound scanning, except one who had thyroid hypopla-
sia.32 The clinical phenotype of these individuals is not readily
distinguishable from those with compensated TSH resistance
who are homozygous or compound heterozygous for muta-
tions in the TSHR gene. Thus in families where non-
autoimmune subclinical hypothyroidism appears to be
inherited in an autosomal dominant manner, the possibility
of a heterozygous mutation in the TSHR should be
considered.
THYROID DYSGENESIS AND SYNDROMIC
CONGENITAL HYPOTHYROIDISM
Evidence to date suggests that the development of the
embryonic thyroid gland and its normal migration is
dependent on the interplay between several transcription
factors. In the thyroid gland, the target genes of these
transcription factors include the thyroglobulin and thyroid
peroxidase (TPO) genes. Transcription factors that have been
studied in human congenital hypothyroidism include TTF-1,
TTF-2, and the paired homeodomain factor Pax-8. In mice,
the expression of TTF-1, TTF-2, and Pax-8 begins at the onset
of thyroid migration on day 9.5 of gestation and these factors
continue to be expressed throughout embryonic develop-
ment.15 36 37 The onset of thyroid differentiation is heralded by
the expression of TSHR, TPO, and TG on day 14.5 of mouse
gestation.
TTF-2 is a transcription factor that is a member of the
forkhead/winged helix domain protein family, many of
which are key regulators of embryonic pattern formation
and regional specification.36 It is a phosphoprotein that
consists of an N terminal region, a highly conserved forkhead
domain, an a helical polyalanine tract, and unique C terminal
residues.38 Unlike some other transcription factors, such as
HOX D13, polymorphism in the size of the polyalanine tract
in TTF-2 has been shown not to affect its transcriptional
function.38 The human gene is located in chromosome 9q22
and consists of a single exon.39 Animal studies have
demonstrated the critical role of TTF-2 in thyroid embryonic
development. Heterozygous Titf-2 knockout mice are euthyr-
oid, with no visible phenotype, whereas homozygous null
mice have cleft palate and thyroid dysgenesis, consisting of
either thyroid agenesis or an ectopic sublingual gland, which
is often lethal in the neonatal period.40 In mouse embryos,
Titf-2 is known to be expressed not only in the thyroid gland
but also in the craniopharyngeal ectoderm involved in palate
formation and in Rathke’s pouch.36 More recently, its
expression has also been demonstrated in pharyngeal
endoderm derivatives, such as tongue, palate, epiglottis,
and oesophagus, and in choanae and whisker follicle in the
mouse and in human thyroid, hair follicle, and prepubertal
testis.41 42
Two Welsh male siblings with a constellation of defects
similar to those in the homozygous knockout mice (con-
genital hypothyroidism associated with thyroid agenesis and
cleft palate)—with added features of spiky hair, bilateral
choanal atresia, and hypoplastic bifid epiglottis43—were
investigated for defects in human TITF-2 (also known as
FKHL15 or FOXE1) and found to be homozygous for a
missense mutation (A65V) within its highly conserved
forkhead DNA binding domain.39 The mutant TTF-2 protein
showed impaired DNA binding and loss of transcriptional
function. This report represented the first description of a
381
genetic cause for thyroid agenesis in humans. Subsequently,
two siblings were studied from an unrelated consanguineous
family, with a milder phenotype consisting of thyroid
agenesis, cleft palate, and spiky hair, but with absence of
choanal atresia and bifid epiglottis (fig 2).44 They were
homozygous for a different missense mutation (S57N) in the
forkhead domain of TTF-2, and the S57N mutant protein
showed only partial loss of DNA binding and transcriptional
activity in vitro, possibly explaining the incomplete clinical
phenotype.
TTF-1 is a homeobox transcription factor of the NK-2 gene
family which is related to Drosophila NK-2/vnd (ventral
nervous system defective).45 The homeobox gene superfamily
encodes transcription regulatory proteins that act at critical
points in development and ontogeny by sequence specific
DNA binding, mediated by a structurally conserved homeo-
domain.46 TTF-1 has two independent transcriptional activa-
tion domains located at the amino terminal (N domain) and
the carboxy terminal (C domain) regions with respect to the
DNA binding homeodomain.47 The human locus is found on
chromosome 14q13, and the gene (also known as NKX-2.1)
comprises three exons encoding a 42 kDa protein.48
Initial evidence of a role for TTF-1 (also known as thyroid
specific enhancer binding protein, T/EBP) in the aetiology of
congenital hypothyroidism also came from a report of a
mouse model in which the Titf-1 gene had been disrupted by
homologous recombination.49 Heterozygous animals were
initially described as having a normal euthyroid phenotype
but more recently were found to have reduced motor
coordination skills when compared with wild type mice.50
Mice homozygous for the Titf-1 gene knockout were born
dead, lacking lung parenchyma, with absent thyroid and
entire pituitary glands, and with extensive defects in the
ventral forebrain.
Not unexpectedly, TTF-1 is expressed in the lungs and
ventral forebrain, in addition to the thyroid gland.51 It is
known to regulate the transcription of TG and TPO genes, the
TSHR gene in thyroid follicular cells,52 53 and the surfactant
protein B (SPB) gene in epithelial lung cells.54 A role for TTF-1
in human respiratory development has been borne out by
reports of heterozygous de novo TITF-1 deletions (14q13–21
and 14q12–13.3, encompassing the TITF-1 locus) and a
mutation (at the 39 splice consensus of intron 2) inherited in
an autosomal dominant manner being associated with
compensated congenital hypothyroidism and unexplained
respiratory distress in term babies in the neonatal period who
had normal bronchial morphology.55–57 The probands had
normal sized eutopic thyroid glands on radionuclide and
ultrasound scanning, and asymmetrical 99mTc uptake was
noted in one report.57 The other prominent recurrent features
associated with either de novo or dominantly inherited
TITF-1 mutations (including one interstitial deletion in
chromosome 14q) are neurological and include hypotonia,
persistent ataxia and dysarthria, microcephaly, choreoathe-
tosis, and global developmental delay, suggesting a role for
TTF-1 in human brain development.57–59 Major feeding
difficulties were also noted. It is thought that the unfavour-
able neurological outcome was most probably related to
TTF-1 deficiency in the thyroid and brain rather than to
inadequately corrected congenital hypothyroidism or inade-
quate thyroxine replacement in an affected mother during
pregnancy. Further data published recently suggest that
TITF-1 mutations, leading to haploinsufficiency, are also
associated with isolated benign hereditary chorea, an
autosomal dominant movement disorder.50
Pax-8 is a transcription factor that is one of the nine
members of the mammalian paired homeodomain family
which recognise DNA through the conserved paired domain
and are homologous to the Drosophila segmentation genes.60
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382
Figure 2 Patients with TITF-2 mutations, showing spiky hair, micrognathia, and hypertelorism (A), and cleft palate (B). (From: Castanet M, et al. A
novel loss-of-function mutation in TTF-2 is associated with congenital hypothyroidism, thyroid agenesis, and cleft palate. Hum Mol Genet
2002;11:20521–9; reproduced by permission of Oxford University Press.)
PAX genes perform key functions in mammalian embryonic
development, during which they show highly restricted
temporal and spatial expression patterns.61 Pax-8 has a
DNA binding domain at the amino terminal end, a carboxy
terminal transcriptional activation domain, and a central
homeodomain.62 The PAX-8 gene maps to human chromo-
some 2q12-q14 and consists of 11 exons.63 Studies have
shown that Pax-8 plays a fundamental role not only in the
initiation of thyroid cell differentiation but also in the
maintenance of the differentiated state, and that it is
essential for thyroid cell proliferation.64 Once again, mouse
models have been instrumental in demonstrating the critical
role of Pax-8 in thyroid organogenesis and thyroid cell
differentiation. Pax-8 null mice have hypoplastic thyroid
glands with absent median anlage derivatives (that is,
follicular cells), whereas lateral anlagen derivatives (para-
follicular calcitonin producing C cells) are present.65
The survival of homozygous mutant mice depends on
thyroxine replacement therapy, whereas heterozygous mice
do not display an obvious thyroid phenotype. In contrast,
heterozygous human PAX-8 mutations have been described in
patients with congenital hypothyroidism of varying severity
in six families: four familial cases where congenital
hypothyroidism appears to be inherited in an autosomal
dominant manner and two sporadic cases.66–69 The thyroid
glands in these patients are hypoplastic and sometimes
ectopic in location. In one family, the thyroid gland was of
normal size at birth but failed to develop normally
postnatally, becoming hypoplastic.69 In this family, the
probands also showed decreased iodide trapping, with
a positive perchlorate discharge test in one, initially sug-
gestive of dyhormonogenesis as a basis for congenital hypo-
thyroidism.
TPO is known to be particularly dependent on Pax-8 for
efficient transcription, and therefore reduced TPO expression
secondary to impaired Pax-8 function may be an explanation
for the partial organification defect.64 Renal hemiagenesis
was also reported in two affected cases, one being associated
with hypercalciuria.59 69 When present, renal agenesis was
ipsilateral to thyroid hemiagenesis.59 Thus congenital
hypothyroidism caused by PAX-8 mutations can occur as
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Park, Chatterjee
non-syndromic or syndromic congenital hypothyroidism.
Outside the thyroid gland, Pax-8 is also expressed in the
kidney, where it is known to activate the Wilms’ tumour gene
(WT1) promoter, and in the developing brain.70 Marked
phenotypic variability has been found within affected
families, suggesting varied penetrance and expressivity of
PAX-8 gene defects.
All mutations to date have been located in the conserved
paired domain of PAX-8, and the mutant proteins have been
shown to have markedly reduced DNA binding with
subsequent loss of transcriptional activation function. At
the structural level, these mutations are thought to disrupt
the pronounced gain of a helical content following interac-
tion of Pax-8 with DNA—that is, impairment of the
unstructured to structured transition that occurs during
DNA recognition (loss of ‘‘induced fit’’).68 Pax-8 activates
transcription of TPO, TG, and NIS, and acts synergistically
with TTF-1 to activate the promoter of human TG gene.70–72
Dominant negative properties of the mutant allele or
haploinsufficiency are not considered likely underlying
mechanisms for pathogenicity of Pax-8 mutations. The exact
mechanism is still unclear but one possibility is that the
human PAX-8 locus is imprinted, with selective expression of
the mutant allele leading to disease.
The stimulatory G protein a subunit gene (GNAS1) is
located on chromosome 20q13 and contains over 13 exons
that encode Gsa, the a subunit of the heterotrimeric
stimulatory G protein which has intrinsic GTPase activity.73
G proteins mediate signal transduction across cell mem-
branes, coupling extracellular receptors—including those
binding TSH, TRH, parathyroid hormone (PTH), and luteinis-
ing hormone—to intracellular effector proteins such as ion
channels and the adenylyl cyclase and phospholipase C
second messenger systems.74 Heterozygous inactivating
mutations in GNAS1 result in Albright hereditary osteo-
dystrophy. This is an autosomal dominant disorder char-
acterised by recognisable dysmorphic features including short
stature, shortened fourth and fifth metacarpals and meta-
tarsals, obesity, subcutaneous ossification, intracranial calci-
fication, and variable mental retardation. Presumably owing
to imprinting mechanisms there is an apparent parent of
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Genetics of congenital hypothyroidism
origin effect whereby maternal transmission usually leads to
a pseudohypoparathyroidism type Ia (PHPIa) phenotype,
while mutations of paternal origin result in pseudopseudo-
hypoparathyroidism (PPHP).75 PHPIa consists of end organ
resistance to multiple hormones including PTH and TSH,
leading to low serum calcium and raised levels of phosphate,
PTH, and TSH, whereas PPHP patients have Albright
hereditary osteodystrophy with a normal biochemical profile.
The degree of TSH resistance tends to be mild, and overt
clinical hypothyroidism is not always present. The TSH
response to TRH is exaggerated and the degree of TSH
resistance may increase with age.76
DYSHORMONOGENESIS AND CONGENITAL
HYPOTHYROIDISM
The end product of a normally developed hypothalamic-
pituitary-thyroid axis is the production of thyroid hormones.
Iodide is actively transported and concentrated in the thyroid
gland by the sodium iodide symporter present in the
basolateral membrane of thyroid follicular cells (fig 3).
Subsequently it is oxidised by hydrogen peroxide and bound
to tyrosine residues in thyroglobulin to form iodotyrosine
(iodide organification). Some of these hormonally inert
iodotyrosine residues (monoiodotyrosine and diiodotyrosine)
couple to form the hormonally active iodothyronines, T4 and
T3. Thyroid peroxidase (TPO) catalyses the oxidation,
organification, and coupling reactions. Defects in any of
these steps lead to dyshormonogenesis which typically
manifests as congenital hypothyroidism and goitre,77 and
the responsible gene at each step has been cloned. Except in
rare cases, all mutations in these genes appear to be inherited
in an autosomal recessive fashion.
TSH
Basolateral I–
NIS T4, T3
membrane
TSHR
H2O2 I–
Thyroid follicular cell
I congenital hypothyroidism associated with colloid deficient
Pendrin
I–
ThOX TPO
Iodotyrosine
TG
I–
Apical Iodotyrosine
TPO
membrane
T4, T3
Lumen
Figure 3 Schematic diagram of a follicular cell, illustrating the steps
involved in thyroid hormone synthesis. TSH receptor (TSHR) bound to
TSH stimulates iodide transport into the thyroid gland by the sodium
iodide symporter (NIS). Subsequently, iodide is oxidised by hydrogen
peroxide, generated by the recently discovered NADPH oxidase system
(ThOX) and bound to tyrosine residues in thyroglobulin (TG) to form
iodotyrosine (iodide organification). Some of these hormonally inactive
iodotyrosine residues (monoiodotyrosine and diiodotyrosine) couple to
form the hormonally active iodothyronines, T4 and T3. Thyroid
peroxidase (TPO) catalyses the oxidation, organification, and coupling
reactions. The exact function of pendrin, a chloride-iodide transporter, in
thyroid hormone synthesis is as yet unknown but it is thought to transport
iodide into the colloid from the thyrocyte. Defects in any of these steps
lead to dyshormonogenesis, which manifests clinically as congenital
hypothyroidism with goitre.
383
TPO, the enzyme responsible for iodide oxidation, organi-
fication, and iodotyrosine coupling, is a 933 amino acid,
membrane bound, glycated, haem containing protein, located
on the apical membranes of the thyroid follicular cell.77 The
human TPO gene is located on chromosome 2p25 and covers
approximately 150 kb of DNA.78 The most prevalent cause of
dyshormonogenesis is TPO deficiency.79 Defects in the TPO
gene have been reported to cause congenital hypothyroidism
by a total iodide organification defect.80 Increasing numbers
of mutations—including maternal isodisomy for chromo-
some 2p—have been reported, occurring throughout the 17
exons of the thyroid peroxidase gene, each resulting in an
inactive TPO protein.80–91 There is one report of metastatic
thyroid carcinoma arising within a congenital goitre asso-
ciated with a mutation in the TPO gene.85
Thyroglobulin is a homodimer with subunits of 330 000
Da, which is synthesised exclusively in the thyroid gland. The
human gene is greater than 300 000 bp in size and is located
on chromosome 8q24.92 The coding sequence is divided into
42 exons, each of about 200 bp in size, except that exon 9 and
10 contain 1101 p and 588 bp, respectively.77 Thyroglobulin
defects arising from mutations in the gene are associated
with moderate to severe congenital hypothyroidism, usually
with low serum thyroglobulin concentrations.93 Affected
individuals often have abnormal iodoproteins in their serum,
especially iodinated albumin, and they excrete iodopeptides
of low molecular weight in the urine.77 There is ineffective
formation of T4 and T3 resulting from a coupling defect.
Owing to its size (coding sequence of 8244 bp), sequencing of
the TG gene has been difficult. However, increasing numbers
of mutations are being reported.94 95 Thyroglobulin is nor-
mally exported through the secretory pathway into the lumen
of thyroid follicles to undergo iodination. Probands with
deficient thyroglobulin resulting from an altered TG coding
sequence have shown defective trafficking of thyroglobulin
from the endoplasmic reticulum to Golgi, leading to an
endoplasmic reticulum storage disease (ERSD).96 A particular
feature of some TG mutations involving cysteine residues in
the protein is disruption of the three dimensional structure of
the molecule, causing it to be retained in the endoplasmic
reticulum as aggregates.96 The cog/cog mouse with a point
mutation in the tg gene, in a region which is strictly
conserved in the thyroglobulin proteins from all known
species, is an example of an ERSD and a model for severe
goitre and abnormal growth and central nervous system
development.97 These mice have aberrant folding, dimerisa-
tion, and export of thyroglobulin, leading to an abnormally
distended endoplasmic reticulum, comparable to that
observed in thyroid biopsies from children with congenital
goitre from defective thyroglobulin synthesis.98 99
NIS is an integral membrane protein of approximately 65
kDa with 12 potential transmembrane domains,100 with both
carboxy and amino termini located inside the cell. Its
expression has not only been detected in normal and
neoplastic thyroid but also in salivary glands, gastric mucosa,
breast, colon, ovaries (lower species), placenta, skin, and
choroid plexus.101 The human gene (NIS) has been mapped to
chromosome 19p, and the coding region contains 15 exons
encoding a protein of 643 amino acids.101 Before the cloning
of NIS, a clinical diagnosis of hereditary iodide transport
defect had been made for several decades on the basis of
goitrous hypothyroidism and absent thyroidal radioiodine
uptake.102 The first demonstration of a loss of function
mutation in the NIS gene was reported in 1997, following
which several mutations inherited in an autosomal recessive
manner have been described.103 The hypothyroidism is of
variable severity (ranging from fully compensated to severe)
and goitre is not always present. Individuals with a higher
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384
dietary iodine intake are less likely to have severe hypothyr-
oidism than those with iodine deficient diets.104 This
condition is therefore preferably treated with iodine supple-
mentation rather than thyroid hormone replacement. People
who are heterozygous for a mutation are euthyroid.103 The
loss of function associated with some of these mutations
(Q267E and S515X) was accounted for by failure of
membrane targeting by the transporter.105
Pendred syndrome is an autosomal recessive disorder
characterised by sensorineural deafness and goitre that was
first described by Vaughn Pendred in 1896. The incidence of
the disease is estimated to be 7.5 to 10 in 100 000, and it is
thought to account for as many as 10% of cases of hereditary
deafness, making it the most common cause of syndromic
deafness.106 Deafness is classically associated with a Mondini
cochlear defect, consisting of a reduced number of turns in
the cochlea, together with an enlarged vestibular aqueduct;
these features are typically present at birth.107 108 Thyroid
disease usually presents as a multinodular or diffuse goitre of
varying size in most affected individuals, and is typically not
evident until the second decade of life. Despite the goitre,
individuals are likely to be euthyroid and only rarely present
with congenital hypothyroidism.109 TSH levels, however, are
often in the upper end of the normal range, and hypothyr-
oidism of variable severity may eventually develop.106
Intrafamilial phenotypic variation has also been noted.110
Affected subjects usually have a positive perchlorate dis-
charge test, with more than 15%—but not complete—release
of radiolabelled iodine following perchlorate administration,
indicating a mild thyroid organification defect.106 A normal
discharge test, on the other hand, does not exclude the
diagnosis.110 The PDS gene is on chromosome 7q, contains 21
exons, and is found to be expressed in the cochlea as well as
in the thyroid.111 It encodes pendrin, a 780 amino acid protein
(molecular weight 86 kDa) with 11 transmembrane domains
which functions as a chloride-iodide transporter.112 In
contrast to the basolateral cell surface expression of NIS,
pendrin has been localised to the apical membrane of a
subset of thyroid follicles.112 It has been hypothesised that
pendrin transports iodide across the apical membrane of the
thyrocyte into the colloid space and that this process is
disrupted in Pendred syndrome, such that iodide is taken up
normally by the thyrocyte but is not efficiently bound to
thyroglobulin in the colloid.113
NADPH oxidases—encoded by two recently cloned genes,
THOX1 and THOX2, located at the apical membrane of
thyrocytes—are involved in H2O2 generation in the thyroid.114
Both genes are highly expressed in thyrocytes.114 Thyroid
peroxidase (TPO) has no biological activity in the absence of
H2O2, which is likely to be the limiting factor for thyroglo-
bulin iodination when iodide supply is normal.115 The two
human THOX genes are arranged in a head to head
configuration and are separated by a 16 kb long region.116
They span 75 kb and are composed of 35 and 34 exons,
respectively. How THOX participates in Ca2+/NADPH depen-
dent H2O2 generation in thyroid tissue is still unknown.
Defects in the human THOX2 have recently been reported,
with heterozygous truncation mutations being associated
with mild transient congenital hypothyroidism and a partial
iodide organification defect, whereas homozygosity for such
defects was associated with severe congenital hypothyroid-
ism and a complete iodide organification defect.117 Goitre was
not detected in these patients.
IODOTHYRONINE TRANSPORTER DEFECTS AND
SYNDROMIC CONGENITAL HYPOTHYROIDISM
TSH secreted by thyrotrophs in the anterior pituitary gland
stimulates the gland to synthesise and secrete thyroid
hormones, principally thyroxine (T4). T4 is essentially a
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Park, Chatterjee
prohormone as it is converted to the biologically more active
hormone triiodothyronine (T3) by 59-monodeiodination in all
tissues. In a negative feedback loop, T3 suppresses TSH
secretion. Thyroid hormone exerts its effects by acting on
nuclear receptors, necessitating transmembrane passage of
the hormone. Several classes of membrane thyroid hormone
transporters have been identified recently, including MCT8,
which was mapped to Xq13.2 and contains five exons.118
There are recent reports of mutations in this gene found in
male individuals in four families with abnormal thyroid
function tests consisting of low FT4 and raised levels of FT3
and TSH, which were not found at the time of neonatal
screening, but detected within the first two years of life.119
Stigmata of congenital hypothyroidism were not present at
birth. In addition, neurological abnormalities from early
infancy were described, consisting of central hypotonia,
peripheral hypertonia, dystonia, rotary nystagmus, dysconju-
gate eye movements, feeding difficulties, vomiting, recurrent
aspiration, irritability, and subsequent spastic quadriplegia
resulting in severe delay in motor and mental development
with absent speech reported in one proband. Brain MRI and
electroencephalography were normal. Thyroid imaging has
not been described. Female relatives harbouring mutations in
MCT8 displayed milder thyroid phenotypes without the
neurological features. Expression of this gene has been found
in all tissues examined, including brain, thyroid, pituitary,
and placenta.119 This is the first example of X linked
congenital hypothyroidism resulting from a defect in target
tissue rather than in the pituitary-thyroid biosynthetic
pathway.
INVESTIGATION AND MANAGEMENT OF
CONGENITAL HYPOTHYROIDISM
In those cases of congenital hypothyroidism where an
underlying genetic defect is suspected—on the basis of
family history, evidence of dyshormonogenesis, or the
presence of other congenital anomalies—to suggest a
syndromic form of the disorder, further investigation can
prove fruitful. While the outcome of such genetic analysis
may not necessarily affect the management of the index
patient, the results can aid genetic counselling regarding
recurrence risk within the family and may suggest the best
treatment option—for example, congenital hypothyroidism
from NIS defects is more amenable to treatment with iodide
supplementation than with thyroxine. We suggest below
some investigations to aid in the search for an underlying
genetic cause in a small number of cases with congenital
hypothyroidism. They are not intended to be a comprehen-
sive list of recommended investigations for physicians
managing routinely diagnosed cases.
As congenital hypothyroidism is largely a sporadic dis-
order, a family history is not present in most cases. However,
a detailed history should be taken, including that of parental
consanguinity, other affected family members, and a history
of any extrathyroidal congenital anomalies (for example,
cleft palate, renal anomalies, neonatal respiratory distress,
and movement disorders). A neonate born with severe
congenital hypothyroidism may have the associated features
of prolonged jaundice, macroglossia, hoarse cry, and umbi-
lical hernia on examination. The neck should be examined
for a goitre and its presence would suggest dyshormonogen-
esis as the basis of congenital hypothyroidism. Rarely, the
goitre can be detected in utero by ultrasound scanning, and
such cases can be treated antenatally by intra-amniotic
injections of thyroxine or triiodothyronine, which can
successfully shrink the gland.120 If a significantly enlarged
goitre escapes antenatal detection, there could be acute
problems postnatally if the upper airway is compromised, and
the expert opinion of a paediatric ENT specialist is vital in
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Genetics of congenital hypothyroidism 385

Transient
? Material anti-TSH receptor antibody
CH
? THOX2
Permanent

History, examination
TFTs, serum TG
Thyroid scintigraphy
Ultrasound scan
Negative perchlorate discharge test
Perchlorate discharge test

Dyshormonogenetic CH Non-dyshormonogenetic CH
Positive perchlorate discharge test
Gland but
↓Serum TG poor tracer
TIOD uptake
Extra-thyroid anomalies
Hearing
loss

? TG ? PDS ? TPO ? NIS Absent

? THOX2
Present
? TSHR
? PAX-8

Cleft palate/spiky hair → ? TITF-2

Renal anomaly → ? PAX-8
Neonatal respiratory distress/chorea/ataxia → ? TITF-1
AHO → ? GNAS1
Other anomalies → ? novel candidate genes

Figure 4 A proposed algorithm for investigating the genetic basis of congenital hypothyroidism. AHO, Albright hereditary osteodystrophy; CH,
congenital hypothyroidism; GNAS, stimulatory G protein a subunit gene; NIS, sodium-iodide symporter gene; PAX-8, human Pax-8 gene; PDS,
Pendred syndrome gene; TFTs, thyroid function tests; TG, thyroglobulin gene; THOX2, thyroid oxidase 2; TIOD, total iodide organification defect;
TITF-1, human TTF-1 gene; TITF-2, human TTF-2 gene; TPO, thyroid peroxidase gene; TSHR, TSH receptor gene; USS, ultrasound scan.

such cases. The presence of any other congenital malforma-
tions should also be sought on examination. Delayed
maturation of bone on x ray is of limited value in infancy
as the ossification centres are composed mainly of cartilage; it
is of greater value after two years in severe forms of
congenital hypothyroidism. The initial crucial steps in
investigating congenital hypothyroidism are to establish the
severity of the hormone defect, to investigate for the
possibility of dyshormonogenesis, and determine the mor-
phology and position of the thyroid gland (fig 4).
Biochemical investigations
The first of these steps is established by obtaining the original
diagnostic thyroid function tests from the neonatal blood
spot screening card and from the first venous serum
measurements, before the onset of L-thyroxine treatment.
In up to 10% of cases, the congenital hypothyroidism is
transient and self limiting, lasting up to a few months.121
Some of these cases can be accounted for by the presence of
anti-TSHR antibodies in the mother, with transplacental
passage to the fetus. When detected, the function of these
TSHR autoantibodies should be measured, as there are
reports of hyperthyroid mothers with Graves’ disease giving
birth to hypothyroid infants.122
In other infants with transient congenital hypothyroidism
and an abnormal perchlorate discharge test suggestive of a
defect in organification within the thyroid, the possibility of
heterozygous mutations in THOX2 should be considered. The
measurement of serum thyroglobulin is also useful as all
patients with organification disorders, and cases with severe
TSHR defects, have raised levels when their circulating TSH is
increased, except in cases with thyroglobulin synthesis defects
where the thyroglobulin level is usually low. Thyroglobulin
measurements can provide useful additional information about
the thyroid gland—for example, if serum thyroglobulin is
measurable where there is apparent athyreosis on thyroid
imaging, this suggests that radiologically undetectable hypo-
plastic thyroid tissue is likely to be present.32
It is also worth checking thyroid function (circulating TSH,
FT4, and FT3) and thyroglobulin levels not only in affected
family members but also in all first degree relatives of
probands, as variable penetrance associated with autosomal
inheritance might lead to the identification of a mildly
affected relative not detected previously. Furthermore, with
TSHR mutations, heterozygotes may also display a mild
phenotype. Underlying autoimmune thyroid disease, causing
raised TSH with low or normal thyroid hormones, can be
excluded by the absence of thyroid autoantibodies. A useful
test to determine whether the thyroid gland is resistant to
TSH involves the administration of TRH, with measurement
of both the pituitary TSH response and the subsequent rise in
circulating T3 following this increase in TSH.
Defective iodide trapping by the thyroid gland caused by
NIS mutations can be tested for by measuring the saliva to
plasma (S/P) ratio of iodide one hour after oral administra-
tion of a small dose of radiolabelled iodide (between 25 and

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386
50 mCi of either 125I or 131I labelled NaI). The normal S/P ratio
is 25 to 140.123 Thyroxine treatment need not be stopped or
reduced before this test, as it does not affect salivary gland
iodide trapping.
Radiological investigations
Thyroid scintigraphy, using either technetium (Tc) or radio-
active iodine, is usually the first line imaging in many centres
and provides information about the size and location of the
gland, but it can be misleading. For example, it can indicate
no uptake of isotope, suggesting apparent athyreosis,
although a thyroid gland is present. Ultrasound scanning of
the neck by an experienced radiologist can provide further
valuable information, with assessment of whether thyroid
gland size is appropriate for age and sex, and its location
along the embryological line of development between the
base of the tongue and thorax. Ultrasound scanning in
conjunction with isotope scanning can provide further useful
information. For example, if there is discordance between
thyroid isotope scanning and ultrasound scanning, with the
former showing no tracer uptake yet the latter showing the
presence of a normal or even an enlarged thyroid gland, there
is strong evidence for the involvement of NIS causing
congenital hypothyroidism. Based on history and initial
investigations, further imaging can be undertaken, such as
a renal ultrasound scan in a family with autosomal dominant
congenital hypothyroidism associated with thyroid gland
hypoplasia (?Pax-8 defect), or MRI of the inner ear in cases of
congenital hypothyroidism with goitre and hearing loss. The
proportion of radioiodine discharged from the thyroid
following the administration of potassium perchlorate is an
index of the severity of organification defects. Discharge of
about 20–45% indicates a partial and mild defect, but values
greater than 60% and 90% are typical of severe and complete
defects, respectively.80
Treatment
Once the diagnosis of congenital hypothyroidism is made on
neonatal screening, appropriate thyroxine replacement ther-
apy is initiated by a paediatrician. Studies have shown that
several variables influence eventual IQ in children with
congenital hypothyroidism. These include the severity of
congenital hypothyroidism (as determined by thyroid func-
tion tests and delayed skeletal maturation at birth), the
dose of thyroxine treatment, the timing of treatment onset,
and serum free thyroxine concentrations during the first
year.124–127 Despite the establishment of neonatal screening
programmes, clinicians and families should be aware of
reports suggesting that about 10% of early treated infants
with severe hypothyroidism are likely to require special
education.128 Therefore clinically significant intellectual
impairment should be actively screened for and treated
when detected in these children.
CONCLUSIONS
Congenital hypothyroidism represents a common neonatal
problem that is easily detected and treated, and hence the
success of the nationwide neonatal screening programmes.
While the great majority of cases are considered sporadic,
there have been recent advances in elucidating some of the
molecular mechanisms behind certain forms of this common
congenital metabolic disorder. Organification defects leading
to goitrous congenital hypothyroidism are now well known to
have an autosomal recessive genetic basis. More recently,
there is growing evidence for the role of germline gene
defects causing congenital hypothyroidism associated with
thyroid dysgenesis. These include a role for the TSHR gene in
non-syndromic congenital hypothyroidism, with evidence for
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Park, Chatterjee
its involvement in recessive disease, and possibly also
heterozygous mutations in this gene in congenital or even
acquired non-autoimmune hypothyroidism. Downstream of
TSHR, defects in Gsa result in TSH resistance in Albright’s
hereditary osteodystrophy. Defects in the transcription
factors TITF-2 (cleft palate, spiky hair), TITF-1 (neonatal
respiratory distress, involuntary movement), and Pax-8 (renal
hemiagenesis) provide the basis for multisystem involvement
in syndromic forms of congenital hypothyroidism. Finally,
there is early evidence emerging for a third group of
congenital hypothyroid conditions associated with defects
in target tissue iodothyronine transporters, with devastating
neurological features.
Novel and as yet unidentified target genes regulated by
these transcription factors may also prove to be important
candidate genes in other forms of congenital hypothyroidism.
A role for the transcription factor Hoxa3 (human locus
7p15.1), a member of the Hox family of homeobox genes
involved in regulating the development of pharyngeal
glandular organs, has hitherto only been shown in murine
embryonic thyroid development, with null mice having
thyroid hypoplasia resulting from defects in both follicular
and parafollicular cell development.129 Interestingly, these
mice also have other abnormalities, including thymic and
parathyroid aplasia, anomalies of the heart and great vessels,
and malformations of the throat and jaw, which are
remarkably similar to those observed in 22q11 deletion
(velocardiofacial) syndrome in humans.130 It is also known
that the amount of thyroid tissue in these patients is variably
reduced, as in the Hoxa3 mutant mice,131 and it has therefore
been suggested that patients with 22q11 deletion syndrome
may be at increased risk of thyroid dysfunction. Hoxa5(2/2)
mutant mice have been reported to have hypothyroidism
associated with transient growth retardation, delayed eye
opening, and ear elevation.132 Thyroid gland development
begins normally, but follicle formation and thyroglobulin
processing are abnormal in late gestation. The expression of
several molecular markers essential for thyroid gland forma-
tion and function—namely TTF-1, Pax8, and TTF-2—is
affected in the developing thyroid gland, with the conse-
quence of altered expression of thyroid effector genes,
including the thyroglobulin and TPO genes. Murine Nkx-
2.5, a member of the homeobox gene superfamily that is
related to the TITF1 (NKX-2.1), is expressed early during
embryogenesis of both thyroid and myocardium,133 and
accordingly represents a strong candidate in those 4% of
cases of congenital hypothyroidism that are associated with
cardiac defects.134
With regard to identification of additional novel candidate
genes, future directions include genome-wide linkage ana-
lyses in large families with multiple probands or parental
consanguinity, identification of congenital hypothyroidism
phenotypes in transgenic or randomly mutagenised mouse
models, and linkage analysis and positional cloning in well
characterised contiguous gene syndromes with congenital
hypothyroidism as a prominent feature (for example, William
syndrome (7q11 deletion) where congenital hypothyroidism
occurs in 25% of affected individuals). Known candidate
genes will have to be carefully ruled out in investigating for
this genetically heterogeneous condition where phenocopies
pose difficulties—for example, in the absence of a family
history it may be difficult to distinguish between TSHR
mutations and Pax-8 defects affecting only the thyroid.
ACKNOWLEDGEMENTS
SMP is a recipient of a Wellcome Trust research training fellowship
for medical and dental graduates and the Raymond and Beverly
Sackler studentship from the University of Cambridge School of
Clinical Medicine.
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Genetics of congenital hypothyroidism
.....................
Authors’ affiliations
S M Park, Department of Clinical Genetics, Addenbrooke’s Hospital,
Cambridge, UK
V K K Chatterjee, Department of Medicine, University of Cambridge,
Addenbrooke’s Hospital
Competing interests: none declared
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Genetics of congenital hypothyroidism

S M Park and V K K Chatterjee

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